KR100779207B1 - N-indolcarbonyl-piperazine derivatives - Google Patents

Abstract

The present invention relates to compounds of formula (I):

[Formula I]

(Wherein R ¹ , R ² , R ⁴ and R ⁵ have the meaning given in claim 1)

It is about. The compound is a potent 5-HT _2A -antagonist and is an eating disorder such as psychosis, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, anorexia nervosa and anorexia nervosa , And premenstrual syndrome and / or obsessive compulsive behavior (delusional-obsessive compulsive disorder, OCD).

Description

N- (indolecarbonyl-) piperazine derivatives {N- (INDOLCARBONYL-) PIPERAZINE DERIVATIVES}

The present invention relates to compounds of formula (I):

(Wherein

R ¹ is unsubstituted or substituted with R ² and / or R ³ a phenyl or naphthyl radical, or Het ¹ ,

R ² , R ³ are each independently Hal, A, OA, OH or CN,

R ⁴ , R ⁵ are each independently H, CN, acyl, Hal, A, OA, OH, CONH ₂ , CONHA or CONA ₂ ,

R ⁴ and R ⁵ together are also alkylene having 3 to 5 carbon atoms,

Het ¹ is a mononuclear or heteronuclear unsaturated heterocyclic system which is unsubstituted or mono- or disubstituted by Hal, A, OA or OH and contains one, two or three identical or different heteroatoms such as nitrogen, oxygen and sulfur ,

A is alkyl having 1 to 6 carbon atoms,

Hal is F, Cl, Br or I,

The indole ring may also be replaced with an isatin unit)

And physiologically acceptable salts and solvates thereof, wherein ( 1H -indol-5-yl)-(4-phenethylpiperazin-1-yl) methanone is excluded.

The present invention aims to find novel compounds with useful properties, in particular properties that can be used in the manufacture of a medicament.

Compounds of formula (I) and their physiologically acceptable salts and solvates have been found to have useful pharmacological properties with good resistance because they act on the central nervous system. This compound has a strong affinity for the 5-HT _2A receptor and also exhibits 5-HT _2A receptor-antagonistic properties.

In order to detect the affinity for the 5-HT _2A receptor in vitro, for example, the following test (Example A1) can be performed. The 5-HT _2A receptor is exposed to [ ³ H] ketanserin (a substance with known affinity for the receptor) and test compounds. The decrease in affinity of [ ³ H] ketanthrine for the receptor is an indication of the affinity of the test substance for the 5-HT _2A receptor. Detection is analogous to that described in JE Leysen et al., Molecular Pharmacology, 1982, 21: 301-314 or for example EP 0320983.

The efficacy of the compounds according to the invention as 5-HT _2A receptor antagonists is described in W. Feniuk et al., Mechanisms of 5-hydroxytryptamine-induced vasoconstriction, in: The Peripheral Actions of 5-Hydroxytryptamine, ed.Fozard JR, Oxford University Press, New York, 1989, p. 110) can be measured in vitro. Thus, the contractility of the rat tail artery, caused by 5-hydroxytryptamine, is mediated by the 5-HT _2A receptor. In the test system, a vascular ring made from the rat tail artery is perfused with an oxygen-saturated solution in an organ bath. By introducing into the solution with increasing concentration of 5-hydroxytryptamine, a response to the cumulative concentration of 5-HT is obtained. The test compound is then added to the engine bath at the appropriate concentration and the second concentration curve is measured for 5-HT. The strength of the test compound against shifting the 5-HT-induced concentration curve to higher 5-HT concentrations is a measure of 5-HT _2A receptor-antagonistic properties in vitro.

5-HT _2A -antagonistic properties can be measured in vivo similarly to MDSerdar et al., Psychopharmacology, 1996, 128: 198-205.

Likewise, other compounds that exhibit 5-HT ₂ -antagonism are described, for example, in EP 0320983.

Similar piperazine derivatives with anti-arrhythmic properties are described, for example, in EP 0431945. Other indolecarbonyl derivatives with analgesic properties are described in EP 0599240. WO 99-11641 describes phenylindole derivatives having 5-HT ₂ -antagonistic properties.

Thus, the compounds of formula (I) are suitable for both animal or human medicaments for treating functional disorders of the central nervous system and also for inflammation. This compound can be used for the prevention and inhibition of cerebral infarction (stroke) sequelae such as seizures and cerebral anemia and extrapyramidal motor neuron side effects and also for the treatment of Parkinson's disease, for the treatment of acute and symptomatic Alzheimer's disease, and for the treatment of atrophic lateral sclerosis have. Likewise, this compound is suitable as a therapeutic agent for the treatment of brain and spinal cord trauma. However, these compounds may be used for decongestants, antidepressants, antipsychotics, neuroleptics, antihypertensives and / or compulsive behavior (delusional-obsessive compulsive disorder, OCD; for example WO 9524194), anxiety states and for example Physiological changes, anxiety, panic attacks, psychosis, schizophrenia, anorexia, delusions, agoraphobia, migraine, Alzheimer's disease, sleep disorders, and also accompanied by anxiety conditions such as rash, tremor or sweating (e.g. EP 319962). Eating disorders such as sleep apnea, delayed dyskinesia, learning disorders, aging-related memory disorders, and macrophages, such as drug abuse such as alcohol, opiates, nicotine, for example psychostimulants such as cocaine or amphetamines (For example US 6004980), sexual dysfunction, all kinds of pain states and fibromyalgia (eg WO 9946245) are particularly suitable as pharmaceutically active compounds.

Compounds of formula (I) are suitable for the treatment of extrapyramidal side effects (EPS) in neuroleptic drug treatment. EPS is characterized by Parkinson-like symptoms, inability to sit and ataxia (eg EP 337136). This compound also prevents anorexia nervosa, angina, Reynaud phenomenon, treatment of coronary vasospasm, migraine (eg EP 208235), pain and neuralgia (eg EP 320983) , Rett's syndrome with autism, Asperger's syndrome, autism and autism disorders, attention deficit disorder, developmental disorders, hyperactivity with mental development and homology behavioral status (eg WO 9524194 Suitable for the treatment of).

The compound is also suitable for the treatment of endocrine gland disorders such as hyperprolactin disease, as well as vasospasm, thrombosis disorders (eg WO 9946245), hypertension and gastrointestinal disorders.

The compounds are also suitable for the treatment of cardiovascular disorders and also extrapyramidal symptoms as described in WO 99/11641, p. 2, lines 24-30.

The compounds according to the invention are also suitable for lowering intraocular pressure and for treating glaucoma. They are also suitable for the prevention and treatment of symptoms of intoxication upon the administration of ergovaline in animals.

This compound is also suitable for treating cardiovascular disorders (WO 99/11641, page 3, lines 14-15).

The compounds according to the invention can also be used with other active compounds in the treatment of schizophrenia. Possible other active compounds are those mentioned in the literature (WO 99/11641, pp. 13, lines 20-26).

This compound can also be used as an intermediate for the preparation of other pharmaceutically active compounds.

The present invention relates to N- (indolecarbonyl) -piperazine derivatives of formula (I) and physiologically acceptable acid addition salts thereof. The invention also relates to solvates of these compounds, for example hydrates or alcoholates.

The present invention therefore relates to a compound of formula (I) according to claim 1 and a process for the preparation of compounds of formula (I).

A process for the preparation of the compound of formula (I) according to claim 1, except for ( 1H -indol-5-yl)-(4-phenethylpiperazin-1-yl) methanone,

a) a compound of formula II:

(Wherein

L is Cl, Br, I or a free or functionally modified reactive OH group,

R ⁴ and R ⁵ have the meaning set forth in claim 1)

To the compound of formula III:                 

Wherein R ¹ has the meaning indicated in claim 1

Or react with

b) a compound of formula IV:

(Wherein R ⁴ and R ⁵ have the meaning set forth in claim 1)

To the compound of formula V:

L-CH ₂ -CH ₂ -R ¹

Wherein L is Cl, Br, I or a free or functionally modified reactive OH group and R ¹ has the meaning indicated in claim 1

Or react with

c) if appropriate, one of the radicals R ¹ , R ⁴ and / or R ⁵ may be cleaved, for example, with an OA group to form an OH group, and / or by converting a CHO group with a CN group to the other radicals R ¹ , R ⁴ and / or Or convert to R ⁵ ,

And / or the base of formula I obtained is treated with an acid and converted to one of its salts.

The invention also relates to a compound of formula (I) according to claim 1 as a medicament, and physiologically acceptable salts and solvates thereof, wherein ( 1H -indol-5-yl)-(4-phenethylpiperazine- 1-day) methanone is excluded.

The present invention relates in particular to the compounds of formula (I) according to claim 1 and physiologically acceptable salts and solvates thereof as medicaments with 5-HT _2A receptor-antagonism.

The invention also relates to compounds of formula (I) and their enantiomers and diastereomers, and salts thereof.

Indole rings can also be replaced with isatin units. Isatin is isolole = indole-2,3-dione substituted with oxo at the 2- and 3-positions.

For all radicals mentioned several times, for example A or Hal, their meanings are mutually independent.

The radical A is alkyl having 1 to 6, preferably 1, 2, 3 or 4, in particular 1 or 2 carbon atoms. Thus, alkyl is, for example, methyl, in addition ethyl, n-propyl, isopropyl, n-butyl, secondary-butyl or tert-butyl, also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1, 2- or 1,2,2-trimethylpropyl, also trifluoromethyl or pentafluoroethyl.

Acyl preferably has 1 to 6 carbon atoms and is, for example, formyl, acetyl, propionyl, butyryl, also trifluoroacetyl or pentafluoropropionyl.

Alkylene is propylene, butylene or pentylene.

OA is preferably methoxy, also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary-butoxy or tert-butoxy.

Hal is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

R ¹ is unsubstituted, preferably-as indicated-monosubstituted phenyl or naphthyl, specifically preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl , o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl , o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-trifluoromethoxyphenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o- , m- or p-chlorophenyl, o-, m- or p-difluoromethoxyphenyl, o-, m- or p-fluoromethoxyphenyl, also preferably 2,3-, 2,4- , 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3- Tyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2- Methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo-3- Methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bro Parent-, 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bro Morphenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 2,3,4-, 2,3,5 -, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, also preferably 2-nitro-4- Trifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2,5-dimethylphenyl, 2-hydroxy-3,5-dichlorophenyl, 2-fluoro-5- or 4-fluoro-3-tri Fluoromethylphenyl, 4-chloro-2- or 4-chloro-3- Lifluoromethyl-, 2-chloro-4- or 2-chloro-5-trifluoromethylphenyl, 4-bromo-2- or 4-bromo-3-trifluoromethylphenyl, p-iodophenyl, 2-nitro-4-methoxyphenyl, 2,5-dimethoxy-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2,4-dimethyl-3-nitrophenyl, 4-fluoro-3-chloro Phenyl, 4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3 -Bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl or 2,4,6-triisopropylphenyl.

R ¹ is also Het ¹ .

Het ¹ is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrroyl, 1-, 2,4- or 5-imidazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, also preferably 1,2,3-triazole-1-, -4 Or -5-yl, 1,2,4-triazol-1-,-3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazole-4- or- 5-yl, 1,2,4-oxadiazole-3- or -5-yl, 1,3,4-thiadiazole-2- or -5-yl, 1,2,4-thiadiazole- 3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3 Or 4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5 -, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3- , 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisox Sazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7 -Benzo-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6- , 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolin It's work.

R ¹ is phenyl, p-chlorophenyl, p-fluorophenyl, thiophen-2-yl, 5-chlorothiophen-2-yl, 2,5-dichlorothiophen-3-yl and 2- or 3- Furyl is particularly very preferred.

R ⁴ , R ⁵ are each independently H, Hal, alkyl having 1 to 6 carbon atoms, alkoxy or hydroxyl having 1 to 6 carbon atoms, and also cyano or acyl.

R ⁴ is preferably H, Hal, A, OA, OH, CN or acyl. R ⁵ is preferably H.

Preferred compounds of formula (I) are those in which the R ¹ -CH ₂ -CH ₂ -piperazinecarbonyl radical is substituted at the 4-, 5-, 6- or 7-position of the indole ring.

The present invention therefore relates to compounds of formula (I), in which one or more radicals mentioned in particular have one of the above preferred meanings. Some of the preferred groups of compounds may be represented by the lower formulas Ia to Ii corresponding to formula I, wherein radicals not described in detail have the meaning in formula I,

In la, R ¹ is phenyl;

In lb, R ¹ is phenyl unsubstituted or monosubstituted by Hal;

In Ic R ¹ is phenyl monosubstituted with Hal, or Het ¹ ;

In Id, R ¹ is unsubstituted or monosubstituted phenyl, or Het ¹ ;

In Ie, R ¹ is unsubstituted or monosubstituted phenyl, or Het ¹ ,

Het ¹ is an unsaturated hete unsubstituted or mono- or di-substituted with Hal or A

         Is logorie based, one or two identical, such as nitrogen, oxygen or sulfur                 

         Or comprises different heteroatoms;

In If, R ¹ is unsubstituted or monosubstituted phenyl, or Het ¹ ,

R ⁴ and R ⁵ are each independently H, Hal or A,

Het ¹ is an unsaturated hete unsubstituted or mono- or di-substituted with Hal or A

          Is logorie based, one or two identical, such as nitrogen, oxygen and sulfur

          Or include different heteroatoms,

In Ig, R ¹ is unsubstituted or monosubstituted phenyl, or Het ¹ ,

R ⁴ , R ⁵ are each independently H, Hal or A,

R ⁴ and R ⁵ together are also alkylene having 3 to 5 carbon atoms,

Het ¹ is unsubstituted or mono- or disubstituted thienyl with Hal or A or

          Furyl,

In Ih, R ¹ is unsubstituted or monosubstituted phenyl, or Het ¹ ,

R ⁴ is H, Hal, CN, acyl or A,

R ⁵ is H,

R ⁴ and R ⁵ together are also alkylene having 3 to 5 carbon atoms,

Het ¹ is unsubstituted or mono- or disubstituted thienyl by Hal or A

          Or furyl;

In Ii, R ¹ is unsubstituted or monosubstituted phenyl or naphthyl, or

Het ¹

R ⁴ is H, Hal, CN, acyl, A or CONH ₂ ,

R ⁵ is H,

R ⁴ and R ⁵ together are also alkylene having 3 to 5 carbon atoms,

Het ¹ is unsubstituted or mono- or disubstituted thienyl with Hal or A or

          Furyl,

          Wherein the indole ring can be replaced with isatin units)

Compounds of formula (I) and starting materials for preparing them are described in, for example, Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, prepared by John Wiley & Sons, Inc., New York, etc. using known methods, ie, under reaction conditions suitable and known for the reaction. In this case, modification methods known per se and not mentioned in more detail herein may also be used.                 

If desired, the starting materials for the claimed process may be formed in situ so that they can continue to react immediately without separation in the reaction mixture, allowing the compounds of formula (I) to be produced. On the other hand, the reaction can be carried out step by step.

In the compounds of the formulas (II) and (V), the radicals L are preferably Cl or Br, but I, OH or otherwise preferably functionally modified reactive OH groups, in particular alkylsulfonyloxy having 1 to 6 carbon atoms (eg For example, methanesulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2-naphthalenesulfonyloxy) or alternatively, Trichloromethoxy, for example methoxy, ethoxy, propoxy or butoxy, and also alkoxy such as phenoxy.

The compound of formula I is preferably obtained by reacting a compound of formula II with a compound of formula III.

In general, starting materials of formulas (II) and (III) are known, and unknown compounds of formulas (II) and (III) can be readily prepared similarly to known compounds.

The reactions of formulas (II) and (III) proceed according to methods as known in the literature for alkylation or acylation of amines. However, the compound can usually be reacted in the presence of a solvent. Examples of suitable solvents include hydrocarbons such as benzene, toluene and xylene; Ketones such as acetone and butanone; Alcohols such as methanol, ethanol, isopropanol and N-butanol; Ethers such as tetrahydrofuran (THF) or dioxane; Amides such as dimethylformamide (DMF) or N-methylpyrrolidone; Nitriles such as acetonitrile and, if appropriate, also mixtures of these solvents with anything else or mixtures with water. Adding acid binders such as alkali or alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of alkali or alkaline earth metals, preferably weak acids of potassium, sodium or calcium, or with triethylamine, dimethylaniline, pyridine or quinoline It may be desirable to add the same organic base or an excess of piperazine derivatives of formula II. Depending on the conditions used, the reaction time ranges from several minutes to 14 days; The reaction temperature is about 0 to 150 °, generally 20 to 130 °.

In addition, compounds of formula (I) may be prepared by reacting an amine of formula (IV) with a component of formula (V) comprising a radical R ¹ .

In general, the reactive components are known or can be prepared by known methods as already described.

The base of formula I obtained can be converted to the relevant acid addition salt using an acid. Acids suitable for this reaction are acids that produce physiologically acceptable salts. Thus, inorganic acids that can be used include hydrochloric acid such as sulfuric acid, hydrochloric acid or hydrobromic acid, phosphoric acid such as orthophosphoric acid, nitric acid, sulfamic acid, and also organic acids, in particular aliphatic, cycloaliphatic, aromatic aliphatic, aromatic or heterocycles. Monobasic or polybasic carboxylic acids, sulfonic acids or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid , Benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isnicotinic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluene Sulfonic acid, naphthalene monosulfonic acid, naphthalene disulfonic acid and lauryl sulfate.

The free base of formula (I) can be liberated from its salt by treatment with a strong base such as sodium hydroxide or potassium hydroxide, or sodium carbonate or potassium carbonate if no further acid groups are present in the molecule, if necessary. If the compound of formula (I) has a free acid group, it can likewise be treated with a base to form salts. Suitable bases include alkali metal hydroxides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary amines.

The invention also includes psychosis, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, atrophic lateral sclerosis, Alzheimer's disease, eating disorders such as Huntington's disease, gluttony, anorexia nervosa, premenstrual syndrome and / or deterministic effects. The present invention relates to a medicament according to the present invention having 5-HT _2A receptor-antagonistic action for treating obsessive compulsive behavior (delusion-obsessive compulsive disorder, OCD).

The invention also relates to pharmaceutical preparations comprising one or more medicaments according to the invention and also vehicles and / or excipients, if appropriate, and other active compounds, if appropriate.

In this case, the medicament may be combined with one or more solid, liquid and / or semi-liquid vehicles or excipients, if appropriate, with one or more other active compound (s) to form a suitable dosage form.                 

The invention also relates to the use of a compound according to the invention and / or physiologically acceptable salts and solvates thereof for the manufacture of a medicament with 5-HT _2A receptor-antagonism.

The invention also includes psychosis, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, atrophic lateral sclerosis, Alzheimer's disease, eating disorders such as Huntington's disease, gluttony, anorexia nervosa, premenstrual syndrome and / or deterministic effects. Of the compounds according to the invention and / or physiologically acceptable salts and solvates thereof for the preparation of a medicament with 5-HT _2A receptor-antagonism for the treatment of obsessive compulsive behavior (delusion-obsessive compulsive disorder, OCD) It is about a use.

Pharmaceutical formulations can be used as medicaments in human and veterinary medicine. Suitable carrier materials are organic or inorganic substances which are suitable for enteral (eg oral) or parenteral administration or topical application and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohol, polyethylene glycol, Carbohydrates such as gelatin, lactose or starch, magnesium stearate, talc, petrolatum. In particular, tablets, tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, liquids, preferably oily or aqueous solutions, also suspensions, emulsions or implants are used for parenteral administration, ointments , Creams or powders are used for topical application. The novel compounds of the invention can also be lyophilized and the lyophilisates obtained can be used, for example, in the preparation of injectable preparations.                 

Such formulations may be sterilized and / or may include excipients such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, fragrances and / or flavoring agents. have. If desired, this agent may also contain one or more other active compounds, for example one or more vitamins.

In this case, the substances according to the invention are generally administered similarly to known formulations, and preferably can be administered at about 0.1 to 500 mg, in particular 5 to 300 mg per dosage unit. The daily dosage is preferably about 0.01 to 250 mg, in particular 0.02 to 100 mg per kg body weight.

In this case, the substances according to the invention are generally preferably administered at 1 to 500 mg, in particular 5 to 100 mg, per dosage unit. The daily dosage is preferably about 0.02 to 10 mg / kg body weight. However, the specific dosage for each patient may vary depending on various factors, such as the efficacy, age, weight, general health, sex, diet, time of administration and route of administration, rate of excretion, combination of drugs and treatment of the specific compound used. It depends on the severity of the particular disorder. Oral administration is preferred.

Above and below, all temperatures are expressed in degrees Celsius. In the following examples, " normal reaction finish " means the solvent is removed if necessary, water is added if necessary, the pH of the mixture is adjusted to 2-10 according to the composition of the final product, if necessary, ethyl acetate or dichloro Extraction with methane, separation of the organic phase, drying with sodium sulfate, filtration and concentration, and purification of the residue by chromatography and / or crystallization on silica gel.

Example A1

Suspension Preparation of 5-HT _2A Receptor:

The shell of the rat forehead is homogenized in cold buffer. The homogenate is centrifuged at 4 ° C. and 50,000 × g for 10 minutes. The pellet is resuspended in 2.5 ml cold Tris buffer, buffered to 10 ml, centrifuged as above. This pellet is then resuspended in buffer and diluted to obtain a homogenate containing 60 mg of material per ml.

0.1 ml of the suspension, 100 μl of [ ³ H] ketaneserine 5 nM solution, 100 μl of test compound solution (concentrations ranging from 10 ⁻⁵ to 10 ⁻¹⁰ moles per liter) are added to the culture tube and made up to 1 ml with buffer. This tube is incubated at 37 ° C. for 15 minutes. After incubation by immersing the tube in an ice bath, the cooled suspension is filtered through a glass filter in vacuo. The filter is washed three times with 5 ml of cold buffer and then transferred to a scintillation tube. The filter is analyzed by liquid scintillation spectroscopy in 8 ml of Triton X scintillator fluid.

Example 1

A solution obtained by dissolving 2.0 g of 4-carboxyindole and 8.1 g of 2-chloro-1-methylpyridinium iodide in 60 ml of N-methylpyrrolidone (NMP) was dissolved in 2.36 g of 4-phenethylpiperazine and 8.2 g of ethyldiisopropylamine (EDIPA) are treated with a solution dissolved in 20 ml of NMP and then stirred at room temperature for 3 hours. The mixture is finished with the usual reaction to obtain a crude product. It is dissolved in acetone and hydrochloride is precipitated using aqueous hydrochloric acid. After drying, 4.59 g of ( 1H -indol-4-yl)-(4-phenethylpiperazin-1-yl) methanone, hydrochloride, mp 289.3 ° are obtained.

, m.p. 289.3°

, mp 289.3 °

Similarly, the following compounds are obtained.

( 1H -indol-4-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 250 °;

( 1H -indol-4-yl)-[4- (thiophen-2-yl) piperazin-1-yl] methanone,

( 1H -indol-4-yl)-[4- (5-chlorothiophen-2-yl) piperazin-1-yl] methanone,

( 1H -indol-4-yl)-[4- (thiophen-3-yl) piperazin-1-yl] methanone,

( 1H -indol-4-yl)-[4- (2,5-dichlorothiophen-3-yl) piperazin-1-yl] methanone, hydrochloride, mp 166-168 °;

( 1H -indol-5-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone,

( 1H -indol-5-yl)-[4- (thiophen-2-yl) piperazin-1-yl] methanone,

( 1H -indol-5-yl)-[4- (5-chlorothiophen-2-yl) piperazin-1-yl] methanone,

( 1H -indol-5-yl)-[4- (thiophen-3-yl) piperazin-1-yl] methanone,

( 1H -indol-5-yl)-[4- (2,5-dichlorothiophen-3-yl) piperazin-1-yl] methanone,

(3-formyl-1 H -indol-5-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 240.9 °;

( 1H -indol-6-yl)-[4-phenethylpiperazin-1-yl) methanone,

( 1H -indol-6-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 284.0-284.4 °;

( 1H -indol-6-yl)-[4- (thiophen-2-yl) piperazin-1-yl] methanone, hydrochloride, mp 204.2-205.7 °;

( 1H -indol-6-yl)-[4- (5-chlorothiophen-2-yl) piperazin-1-yl] methanone, hydrochloride, mp 251.0-252.5 °;

( 1H -indol-6-yl)-[4- (thiophen-3-yl) piperazin-1-yl] methanone,

( 1H -indol-6-yl)-[4- (2,5-dichlorothiophen-3-yl) piperazin-1-yl] methanone, hydrochloride, mp 240-241 °;

(3-formyl- ( 1H -indol-6-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone,

(3-cyano-1 H -indol-6-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 280 °;

( 1H -indol-7-yl)-[4-phenethylpiperazin-1-yl) methanone, hydrochloride, mp 221 °;

( 1H -indol-7-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 274 °;

( 1H -indol-7-yl)-[4- (thiophen-2-yl) piperazin-1-yl] methanone,

( 1H -indol-7-yl)-[4- (5-chlorothiophen-2-yl) piperazin-1-yl] methanone, hydrochloride, mp 251.0-252.5 °;

( 1H -indol-7-yl)-[4- (thiophen-3-yl) piperazin-1-yl] methanone,

( 1H -indol-7-yl)-[4- (2,5-dichlorothiophen-3-yl) piperazin-1-yl] methanone,

(3-formyl-1 H -indol-7-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone,

Hydrochloride, m.p. 287 °;

(3-cyano- 1H -indol-7-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone,

Hydrochloride, m.p. > 300 °;

(2,3-dimethyl-1 H -indol-7-yl)-(4-phenethylpiperazin-1-yl) methanone,

(2,3-dimethyl-1 H -indol-7-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone, 86.5-89 °;

(2,3-dimethyl-1 H -indol-7-yl)-[4- (thiophen-2-yl) piperazin-1-yl] methanone,

(2,3-dimethyl-1 H -indol-7-yl)-[4- (5-chlorothiophen-2-yl) piperazin-1-yl] methanone,

(2,3-dimethyl-1 H -indol-7-yl)-[4- (thiophen-3-yl) piperazin-1-yl] methanone,

(2,3-dimethyl-1 H -indol-7-yl)-[4- (2,5-dichlorothiophen-3-yl) piperazin-1-yl] methanone,

(6,7,8,9-tetrahydro -5 H-carbazole-3-yl) - (4-phenethyl-piperazin-1-yl) -methanone hydrochloride, mp 235-237 °;

(6,7,8,9-tetrahydro -5 H-carbazole-3-yl) - [4- (4-fluoro-phenethyl) piperazine-1-yl] -methanone,

(6,7,8,9-tetrahydro -5 H-carbazole-3-yl) - [4- (thiophen-2-yl) piperazin-1-yl] -methanone,

(6,7,8,9-tetrahydro -5 H-carbazole-3-yl) - [4- (5-chlorothiophen-2-yl) piperazin-1-yl] -methanone,

(6,7,8,9-tetrahydro -5 H-carbazole-3-yl) - [4- (thiophen-3-yl) piperazin-1-yl] -methanone,

(6,7,8,9-tetrahydro -5 H-carbazole-3-yl) - [4- (2,5-dichloro-thiophen-3-yl) piperazin-1-yl] -methanone,

(3-formyl- ( 1H -indol-6-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone,

Hydrochloride, m.p. 279.3 °;

( 1H -indol-6-yl)-[4- (5-chlorothiophen-2-yl) piperazin-1-yl] methanone, hydrochloride, mp 257.5-259.0 °;

( 1H -indol-4-yl)-[4- (5-chlorothiophen-2-yl) piperazin-1-yl] methanone, hydrochloride, mp 266-267 °;

(3-cyano-1 H -indol-5-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 210 °;

(3-cyano-1 H -indol-7-yl)-[4- (naphth-2-ylethyl) piperazin-1-yl] methanone, hydrochloride, mp 284.0-285.5 °;

(3-cyano-1 H -indol-4-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 284.0-285.5 °;

(3-cyano-1 H -indol-4-yl)-[4- (2-fluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 213-215.5 °;

(3-cyano-1 H -indol-7-yl)-[4- (2-fluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 212.5-214 °;

(3-aminocarbonyl-1 H -indol-7-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 280-281 °;

(3-cyano-1 H -indol-7-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone, methanesulfonate, mp 212.5-214 °;

(3-cyano-1 H -indol-7-yl)-[4- (5-chlorothiophen-2-yl) piperazin-1-yl] methanone, hydrochloride, mp 301.5-303.0 °;

(3-cyano-1 H -indol-7-yl)-[4-phenethyl-piperazin-1-yl) methanone, methanesulfonate, mp 294.7-297 °;

(3-cyano-1 H -indol-7-yl)-[4- (2,4-difluorophenethyl) piperazin-1-yl] methanone, hydrochloride, mp 295.6-297.0 °;

7- {4- [2- (4-fluorophenyl) ethyl] piperazin-1-carbonyl} -1 H -indole-2,3-dione.

The following examples relate to pharmaceutical formulations:

Example A: Vials for Injection

A solution of 100 g of the active compound of formula (I) and 5 g of sodium diphosphate dissolved in 3 l of secondary distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, then sterile filtered, filled into an injection vial, lyophilized and sterilized. Sealed by the method. Injectable vials containing 5 mg of the active compound were obtained.                 

Example B: Suppositories

A mixture of 20 g of active compound of formula I was melted together with 100 g of soya lecithin and 1400 g of cocoa butter, then poured into a mold and cooled. Suppositories containing 20 mg of the active compound were obtained.

Example C: Liquid

Of formula (I) to active compound _{1g, NaH 2 PO 4 × 2H} 2 O 9.38g, NaH 2 PO 4 × 12H 2 0 28.48g and benzalkonium chloride 0.1g to prepare a solution dissolved in distilled water 940㎖. The solution was adjusted to pH 6.8, filled to 1 l and sterilized by radiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of the active compound of formula (I) were mixed with 99.5 g of petrolatum under aseptic conditions.

Example E: Tablets

A tablet was prepared by compressing a mixture of 1 kg of active compound of formula (I), 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc, and 0.1 kg of magnesium stearate in a conventional manner such that each tablet contains 10 mg of active compound.

Example F: Tablets

Similar to Example E, the tablets were compressed and then skinned in a conventional manner using a skinned product consisting of sucrose, potato starch, talc, tragacanth and colorants.

Example G: Capsule

Hard gelatine capsules were filled with 2 kg of the active compound of formula (I) in a conventional manner such that each capsule contained 20 mg of the active compound to prepare a capsule.

Example H: Ampoules

A solution in which 1 kg of the active compound of formula I was dissolved in 60 l of secondary distilled water was charged into an ampoule, lyophilized under sterile conditions and sealed by sterile method. An ampoule containing 10 mg of the active compound was obtained.

Claims (17)

delete delete delete delete delete delete delete delete Compound of Formula (I): [Formula I]

(Wherein R ¹ is unsubstituted or phenyl or naphthyl radical, or Het ¹ , substituted by R ² , R ³ , or R ² and R ³ , respectively, R ² and R ³ are each independently Hal, A, OA, OH or CN, R ⁴ is H, CN, acyl having 1 to 6 carbon atoms, Hal, A, OA, OH, CONH ₂ , CONHA or CONA ₂ , R ⁵ is H, R ⁴ and R ⁵ together are optionally alkylene having 3 to 5 carbon atoms, Het ¹ is unsubstituted or mono- or di-substituted by Hal, A, OA or OH and contains 2 to 9 carbon atoms containing one, two or three identical or different heteroatoms such as nitrogen, oxygen and sulfur Or a heteronuclear unsaturated heterocyclic system, A is alkyl having 1 to 6 carbon atoms, Hal is F, Cl, Br or I, Wherein indole rings may also be replaced with isatin units) And physiologically acceptable salts thereof, wherein (1 H -indol-5-yl) (4-phenethylpiperazin-1-yl) methanone and 1-((5-methoxy-1 H -indole- 7-yl) carbonyl) -4- (2-phenylethyl) piperazine). (a) (3-cyano-1H-indol-7-yl) [4- (4-fluorophenethyl) piperazin-1-yl] methanone,

(b) (3-aminocarbonyl-1H-indol-7-yl) [4- (4-fluorophenethyl) piperazin-1-yl] methanone,

And physiologically acceptable salts thereof. a) a compound of formula II: [Formula II]

(Wherein L is Cl, Br, I or a free or functionally modified reactive OH group, R ⁴ and R ⁵ are as defined in claim 9) To the compound of formula III: [Formula III]

Wherein R ¹ is as defined in claim 9 Or react with b) a compound of formula IV: [Formula IV]

Wherein R ⁴ and R ⁵ are as defined in claim 9 To the compound of formula V: [Formula V] L-CH ₂ -CH ₂ -R ¹ (Wherein L is Cl, Br, I or a free or functionally modified reactive OH group, R ¹ is as defined in claim 9) Reacting with, ( 1H -indol-5-yl) (4-phenethylpiperazin-1-yl) methanone and 1-((5-methoxy- 1H -indol-7-yl) carbonyl) -4- ( A process for preparing the compound of formula (I) according to claim 9 or 10, except for 2-phenethyl) piperazine. delete delete a) a compound of formula II: [Formula II]

(Wherein L is Cl, Br, I or a free or functionally modified reactive OH group, R ⁴ and R ⁵ are as defined in claim 9) To the compound of formula III: [Formula III]

Wherein R ¹ is as defined in claim 9 Or react with b) a compound of formula IV: [Formula IV]

Wherein R ⁴ and R ⁵ are as defined in claim 9 To the compound of formula V: [Formula V] L-CH ₂ -CH ₂ -R ¹ (Wherein L is Cl, Br, I or a free or functionally modified reactive OH group, R ¹ is as defined in claim 9) React with Radicals R ^1, R ⁴ or R ⁵ a to cut an OA form an OH or, characterized in that it comprises the step of switching to a different radical R ^1, R ⁴ or R ⁵ by converting a group CHO group CN more, ( 1 H -indol-5-yl) (4-phenethylpiperazin-1-yl) methanone and 1-((5-methoxy-1 H -indol-7-yl) carbonyl) -4- (2 11. A process for the preparation of compounds of formula (I) according to claim 9 or 10, except for phenethyl) piperazine. a) a compound of formula II: [Formula II]

(Wherein L is Cl, Br, I or a free or functionally modified reactive OH group, R ⁴ and R ⁵ are as defined in claim 9) To the compound of formula III: [Formula III]

Wherein R ¹ is as defined in claim 9 Or react with b) a compound of formula IV: [Formula IV]

Wherein R ⁴ and R ⁵ are as defined in claim 9 To the compound of formula V: [Formula V] L-CH ₂ -CH ₂ -R ¹ (Wherein L is Cl, Br, I or a free or functionally modified reactive OH group, R ¹ is as defined in claim 9) React with If the resulting compound of formula (I) is a base, further comprising converting the resulting compound of formula (I) to an acid and converting it into one of its salts, (1 H -indol-5-yl) ( Except for 4-phenethylpiperazin-1-yl) methanone and 1-((5-methoxy-1 H -indol-7-yl) carbonyl) -4- (2-phenethyl) piperazine Process for the preparation of compounds of formula I according to claim 9 or 10. delete delete